Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome

Ferone, Giustina; Thomason, Helen A.; Antonini, Dario; Rosa, Laura De; Hu, Bing; Gemei, Marica; Zhou, Huiqing; Ambrosio, Raffaele; Rice, David; Acampora, Dario; Bokhoven, Hans van; Vecchio, Luigi Del; Koster, Maranke I.; Tadini, Gianluca; Spencer‐Dene, Bradley; Dixon, Michael J.; Dixon, Jill; Missero, Caterina

doi:10.1002/emmm.201100199

Cited by 66 publications

(96 citation statements)

References 52 publications

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“…How do these data reconcile with previous reports showing that the prostate luminal cell compartment can form and expand in the complete absence of ΔNp63-positive cells? In other tissues, p63 (and specifically ΔNp63) is required to maintain progenitor/stem cells but is dispensable for cell differentiation (19)(20)(21)(22)(23)(24). For instance, the epidermis of p63 −/− embryos at 17 dpc contains clusters of cells expressing the differentiation markers loricrin, filaggrin, and involucrin, indicating that p63-null ectoderm can produce differentiated epidermal cells in the absence of functional progenitors (19,27).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

Pignon

Grisanzio

Geng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

188

194

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The tumor protein p63 (p63), and more specifically the NH2-terminal truncated (ΔN) p63 isoform, is a marker of basal epithelial cells and is required for normal development of several epithelial tissues, including the bladder and prostate glands. Although p63-expressing cells are proposed to be the stem cells of the developing prostate epithelium and bladder urothelium, cell lineages in these endoderm-derived epithelia remain highly controversial, and rigorous lineage tracing studies are warranted. Here, we generated knock-in mice expressing Cre recombinase (Cre) under the control of the endogenous ΔNp63 promoter. Heterozygote ΔNp63 +/Cre mice were phenotypically normal and fertile. Cremediated recombination in ΔNp63 +/Cre ;ROSA26 EYFP reporter mice faithfully recapitulated the pattern of ΔNp63 expression and were useful for genetic lineage tracing of ΔNp63-expressing cells of the caudal endoderm in vivo. We found that ΔNp63-positive cells of the urogenital sinus generated all epithelial lineages of the prostate and bladder, indicating that these cells represent the stem/ progenitor cells of those epithelia during development. We also observed ΔNp63 expression in caudal gut endoderm and the contribution of ΔNp63-positive cells to the stem/progenitor compartment of adult colorectal epithelium. Because p63 is a master regulator of stratified epithelial development, this finding provides a unique developmental insight into the cell of origin of squamous cell metaplasia and squamous cell carcinoma of the colon.large intestine | hindgut | genitourinary tract

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Section: Discussionmentioning

confidence: 99%

“…Specific KO mice for the TA and the ΔNp63 isoforms reveal that these anomalies result from ΔNp63 absence (18,19). Phenotypes in p63 KO or mutant mice result, among other reasons, from apparent defects in stem and progenitors cells' capacity to proliferate or survive (19)(20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

Pignon

Grisanzio

Geng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

188

194

View full text Add to dashboard Cite

show abstract

“…As a transcriptional repressor, p63 maintains proliferation of basal epidermal keratinocytes by directly repressing expression of antiproliferative target genes, including 14-3-3s, p16/Ink4a, p19/Arf, p21, and PTEN (Westfall et al 2003;Watt et al 2008;Su et al 2009a;Leonard et al 2011;Ferone et al 2012). In addition to cellcycle-associated genes, p63 inhibits the expression of nonkeratinocyte genes (i.e., mesodermal genes), as well as a number of other genes such as distinct components of the Notch (Notch1, Hes1) and bone morphogenetic protein (BMP) signaling pathways (Smad7) in epidermal keratinocytes (Nguyen et al 2006;De Rosa et al 2009;Shalom-Feuerstein et al 2011).…”

Section: Va Botchkarev and Er Floresmentioning

confidence: 99%

p53/p63/p73 in the Epidermis in Health and Disease

Botchkarev

Flores

2014

Cold Spring Harbor Perspectives in Medicine

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Although p53 has long been known as the "guardian of the genome" with a role in tumor suppression in many tissues, the discovery of two p53 ancestral genes, p63 and p73, more than a decade ago has triggered a considerable amount of research into the role of these genes in skin development and diseases. In this review, we primarily focus on mechanisms of action of p53 and p63, which are the best-studied p53 family members in the skin. The existence of multiple isoforms and their roles as transcriptional activators and repressors are key to their function in multiple biological processes including the control of skin morphogenesis, regeneration, tumorigenesis, and response to chemotherapy. Last, we provide directions for further research on this family of genes in skin biology and pathology.

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“…6). Although these changes can be explained by the loss of function of the TI domain, the SAM domain also plays a key role in regulating p63 function in vivo (Ferone et al, 2012). Thus, it will be important to determine the specific roles of the p63 SAM and p63 TI domains and whether a mutation in one domain affects the function (s) of the other during development.…”

Section: Discussionmentioning

confidence: 99%

“…The significance of Cα is evident from genetic studies of p63-associated EDs, showing that mutations in either the p63 SAM or p63 TI domain or a complete absence of Cα/β but not Cγ cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome and limb-mammary syndrome (LMS) (Barrow et al, 2002;Celli et al, 1999;Rinne et al, 2009;van Bokhoven et al, 2001). A recent study has shown that a point mutation in the p63 SAM domain reduces the number of epidermal progenitor cells (Ferone et al, 2012), highlighting the significance of Cα in regulating stem cell properties. However, how Cα exerts its function and the relative contribution of Cα in TAp63 and ΔNp63 isoform functions remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

The carboxy-terminus of p63 links cell cycle control and the proliferative potential of epidermal progenitor cells

et al. 2015

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The transcription factor p63 (Trp63) plays a key role in homeostasis and regeneration of the skin. The p63 gene is transcribed from dual promoters, generating TAp63 isoforms with growth suppressive functions and dominant-negative ΔNp63 isoforms with opposing properties. p63 also encodes multiple carboxy (C)-terminal variants. Although mutations of C-terminal variants have been linked to the pathogenesis of p63-associated ectodermal disorders, the physiological role of the p63 C-terminus is poorly understood. We report here that deletion of the p63 C-terminus in mice leads to ectodermal malformation and hypoplasia, accompanied by a reduced proliferative capacity of epidermal progenitor cells. Notably, unlike the p63-null condition, we find that p63 C-terminus deficiency promotes expression of the cyclin-dependent kinase inhibitor p21Waf1/Cip1 (Cdkn1a), a factor associated with reduced proliferative capacity of both hematopoietic and neuronal stem cells. These data suggest that the p63 C-terminus plays a key role in the cell cycle progression required to maintain the proliferative potential of stem cells of many different lineages. Mechanistically, we show that loss of Cα, the predominant C-terminal p63 variant in epithelia, promotes the transcriptional activity of TAp63 and also impairs the dominantnegative activity of ΔNp63, thereby controlling p21 Waf1/Cip1 expression. We propose that the p63 C-terminus links cell cycle control and the proliferative potential of epidermal progenitor cells via mechanisms that equilibrate TAp63 and ΔNp63 isoform function.

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Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome

Cited by 66 publications

References 52 publications

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

p53/p63/p73 in the Epidermis in Health and Disease

The carboxy-terminus of p63 links cell cycle control and the proliferative potential of epidermal progenitor cells

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